Genomic selection signatures in autism spectrum disorder identifies cognitive genomic tradeoff and its relevance in paradoxical phenotypes of deficits versus potentialities

AbstractAutism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by paradoxical phenotypes of deficits as well as gain in brain function. To address this a genomic tradeoff hypothesis was tested and followed up with the biological interaction and evolutionary significance of positively selected ASD risk genes. SFARI database was used to retrieve the ASD risk genes while for population datasets 1000 genome data was used. Common risk SNPs were subjected to machine learning as well as independent tests for selection, followed by Bayesian analysis to identify the cumulative effect of selection on risk SNPs. Functional implication of these positively selected risk SNPs was assessed and subjected to ontology analysis, pertaining to their interaction and enrichment of biological and cellular functions. This was followed by comparative analysis with the ancient genomes to identify their evolutionary patterns. Our results identified significant positive selection signals in 18 ASD risk SNPs. Functional and ontology analysis indicate the role of biological and cellular processes associated with various brain functions. The core of the biological interaction network constitutes genes for cognition and learning while genes in the periphery of the network had direct or indirect impact on brain function. Ancient genome analysis identified de novo and conserved evolutionary selection clusters. The de-novo evolutionary cluster represented genes involved in cognitive function. Relative enrichment of the ASD risk SNPs from the respective evolutionary cluster or biological interaction networks may help in addressing the phenotypic diversity in ASD. This cognitive genomic tradeoff signatures impacting the biological networks can explain the paradoxical phenotypes in ASD.

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Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder

10.1101/083428 ◽

2017 ◽

Cited By ~ 2

Author(s):

Deidre R. Krupp ◽

Rebecca A. Barnard ◽

Yannis Duffourd ◽

Sara A. Evans ◽

Ryan M. Mulqueen ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

De Novo ◽

Large Family ◽

Recurrence Risk ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Sequencing Data ◽

Full Cohort ◽

Risk Genes ◽

Family Based

AbstractGenetic risk factors for autism spectrum disorder (ASD) have yet to be fully elucidated. Postzygotic mosaic mutations (PMMs) have been implicated in several neurodevelopmental disorders and overgrowth syndromes. We systematically evaluated PMMs by leveraging whole-exome sequencing data on a large family-based ASD cohort, the Simons Simplex Collection. We found evidence that 11% of published single nucleotide variant (SNV) de novo mutations are potentially PMMs. We then developed a robust SNV PMM calling approach that leverages complementary callers, logistic regression modeling, and additional heuristics. Using this approach, we recalled SNVs and found that 22% of de novo mutations likely occur as PMMs in children. Unexpectedly, we found a significant burden of synonymous PMMs in probands that are predicted to alter splicing. We found no evidence of missense PMM burden in the full cohort. However, we did observe increased signal for missense PMMs in families without germline mutations in probands, which strengthens in genes intolerant to mutations. We also determined that 7-11% of parental mosaics are transmitted to children. Parental mosaic mutations make up 6.8% of all mutations newly germline in children, which has important implications for recurrence risk. PMMs intersect previously implicated high confidence and other ASD candidate risk genes, further suggesting that this class of mutations contribute to ASD risk. We also identified PMMs in novel candidate risk genes involved with chromatin remodeling or neurodevelopment. We estimate that PMMs contribute risk to 4-8% of simplex ASD cases. Overall, these findings argue for future studies of PMMs in ASD and related-disorders.

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Genetic contributions to autism spectrum disorder

Psychological Medicine ◽

10.1017/s0033291721000192 ◽

2021 ◽

pp. 1-14

Author(s):

A. Havdahl ◽

M. Niarchou ◽

A. Starnawska ◽

M. Uddin ◽

C. van der Merwe ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Rare Variants ◽

De Novo ◽

Point Mutations ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Individual Risk ◽

Future Research ◽

Risk Genes

Abstract Autism spectrum disorder (autism) is a heterogeneous group of neurodevelopmental conditions characterized by early childhood-onset impairments in communication and social interaction alongside restricted and repetitive behaviors and interests. This review summarizes recent developments in human genetics research in autism, complemented by epigenetic and transcriptomic findings. The clinical heterogeneity of autism is mirrored by a complex genetic architecture involving several types of common and rare variants, ranging from point mutations to large copy number variants, and either inherited or spontaneous (de novo). More than 100 risk genes have been implicated by rare, often de novo, potentially damaging mutations in highly constrained genes. These account for substantial individual risk but a small proportion of the population risk. In contrast, most of the genetic risk is attributable to common inherited variants acting en masse, each individually with small effects. Studies have identified a handful of robustly associated common variants. Different risk genes converge on the same mechanisms, such as gene regulation and synaptic connectivity. These mechanisms are also implicated by genes that are epigenetically and transcriptionally dysregulated in autism. Major challenges to understanding the biological mechanisms include substantial phenotypic heterogeneity, large locus heterogeneity, variable penetrance, and widespread pleiotropy. Considerable increases in sample sizes are needed to better understand the hundreds or thousands of common and rare genetic variants involved. Future research should integrate common and rare variant research, multi-omics data including genomics, epigenomics, and transcriptomics, and refined phenotype assessment with multidimensional and longitudinal measures.

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Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

10.1101/2020.09.09.20187104 ◽

2020 ◽

Author(s):

Holly K. Harris ◽

Tojo Nakayama ◽

Jenny Lai ◽

Boxun Zhao ◽

Nikoleta Argyrou ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Attention Deficit Hyperactivity Disorder ◽

Transcription Factors ◽

Intellectual Disability ◽

Attention Deficit ◽

De Novo ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Risk Genes ◽

Hyperactivity Disorder

Purpose: We describe a novel neurobehavioral syndrome of autism spectrum disorder, intellectual disability, and attention deficit/hyperactivity disorder associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. Methods: We assembled a cohort of 36 individuals (from 31 unrelated families) with de novo mutations in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. Results: These individuals share neurobehavioral features including autism spectrum disorder (ASD), intellectual disability, and attention-deficit/hyperactivity disorder (ADHD); other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. Conclusion: These results establish deleterious variation in RFX3, RFX4, and RFX7 as important causes of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.

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Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

Molecular Brain ◽

10.1186/s13041-021-00769-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Kohei Kitagawa ◽

Kensuke Matsumura ◽

Masayuki Baba ◽

Momoka Kondo ◽

Tomoya Takemoto ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social Behavior ◽

Mouse Model ◽

Mouse Models ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

De Novo Mutation ◽

Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

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A de novo mosaic mutation in SPAST with two novel alternative alleles and chromosomal copy number variant in a boy with spastic paraplegia and autism spectrum disorder

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2017.07.015 ◽

2017 ◽

Vol 60 (10) ◽

pp. 548-552 ◽

Cited By ~ 3

Author(s):

A.M. Matthews ◽

M. Tarailo-Graovac ◽

E.M. Price ◽

I. Blydt-Hansen ◽

A. Ghani ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Copy Number ◽

De Novo ◽

Copy Number Variant ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Spastic Paraplegia ◽

Chromosomal Copy Number ◽

Chromosomal Copy

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Increased burden of deleterious variants in essential genes in autism spectrum disorder

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1613195113 ◽

2016 ◽

Vol 113 (52) ◽

pp. 15054-15059 ◽

Cited By ~ 30

Author(s):

Xiao Ji ◽

Rachel L. Kember ◽

Christopher D. Brown ◽

Maja Bućan

Keyword(s):

Autism Spectrum Disorder ◽

Large Scale ◽

De Novo ◽

Autism Spectrum ◽

Essential Genes ◽

Spectrum Disorder ◽

Model Organisms ◽

Disease Genes ◽

Priority List ◽

Human Orthologs

Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre- and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.

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